The invention relates to porous polymeric materials to which chemical or biological moieties have been attached, and methods for making the same.
Porous polymeric materials can be used in a variety of applications. Their uses include medical devices that serve as substitute blood vessels, synthetic and intraocular lenses, electrodes, catheters, and extracorporeal devices such as those that are connected to the body to assist in surgery or dialysis. Porous polymeric materials can also be used as filters for the separation of blood into component blood cells and plasma, microfilters for removal of microorganisms from blood, and coatings for opthalmic lenses to prevent endothelial damage upon implantation.
Bonding materials other than polymers to porous polymeric materials can alter the properties of porous polymers. A combination of properties may provide porous polymers suitable for the above mentioned purposes. This combination, however, has been difficult to achieve because of the natural properties of polymers.
The hydrophobic nature of typical polymers, however, has limited the usefulness of porous materials made from them. For example, proteins will often denature when placed in contact with such materials. But contact lenses, implants, and related devices that are in intimate contact with the body must have hydrophilic surfaces that are biologically compatible.
The physical and/or chemical properties of a plastic surface can be changed by adhering or bonding a different material to it. Examples of this technique are disclosed by U.S. Pat. No. 4,619,897, which is directed to a porous resin membrane, and by U.S. Pat. No. 4,973,493, which is directed to a device with a biocompatible surface. Other examples of surface modification are provided by U.S. Pat. Nos. 5,077,215, 5,183,545, and 5,203,997, which disclose the adsorption of anionic and nonionic fluorocarbon surfactants onto the surface of fluorocarbon support members.
Further examples of surface modification can be found in U.S. Pat. No. 5,263,992, which discloses the adsorption of polymeric chains onto a support member, and in U.S. Pat. No. 5,308,641, which discloses the covalent attachment of a polyalkylimine to an aminated substrate.
Despite the different techniques available for modifying the surface of polymeric materials, most are limited in their ability to control the degree to which a surface is modified, and many are expensive, inefficient, or cannot be use to modify porous surfaces without coating or clogging their pores. A need exists for polymeric materials that can alter their functionality depending upon incorporation of additives and/or post treatment of these additives. The present invention provides new porous polymeric materials and methods of their manufacture that address this need.
This invention encompasses novel porous materials and methods of their manufacture. Materials of the invention comprise a porous substrate to which chemical or biological moieties are bound directly or by a spacer.
A first embodiment of the invention encompasses a material comprising: a porous substrate comprised of a polymer and a functional additive and having a surface, wherein the surface comprises a region defined by at least some of the functional additive; and a biological or chemical moiety covalently or non-covalently bound to the region. In a preferred material encompassed by this embodiment, the surface comprises a plurality of regions defined by at least some of the functional additive, each of which is covalently bound to a chemical or biological moiety.
A second embodiment of the invention encompasses a material comprising: a porous substrate comprised of a polymer and a functional additive and having a surface, wherein the surface comprises a region defined by at least some of the functional additive; a spacer covalently or non-covalently bound to the region; and a biological or chemical moiety covalently or non-covalently bound to the spacer. In a preferred material encompassed by this embodiment, the surface comprises a plurality of regions defined by at least some of the functional additive, each of which is covalently bound a spacer, which in turn is bound to a biological moiety.
Examples of polymers from which materials of the invention can be made include, but are not limited to, polyolefins, polyethers, nylons, polycarbonates, poly(ether sulfones), or mixtures thereof. Polyethers include, but are not limited to, polyether ether ketone (PEEK, poly(oxy-1,4-phenylene-oxy-1,4-phenylene-carbonyl-1,4-phenylene)), polyether sulfone (PES), or mixtures thereof. Polyolefins include, but are not limited to, ethylene vinyl acetate; ethylene methyl acrylate; polyethylenes; polypropylenes; ethylene-propylene rubbers; ethylene-propylene-diene rubbers; poly(l-butene); polystyrene; poly(2-butene); poly(1-pentene); poly(2-pentene); poly(3-methyl-1-pentene); poly(4-methyl-1-pentene); 1,2-poly-1,3-butadiene; 1,4-poly-1,3-butadiene; polyisoprene; polychloroprene; poly(vinyl acetate); poly(vinylidene chloride); poly(tetrafluoroethylene) (PTFE); poly(vinylidene fluoride) (PVDF); acrylonitrile-butadiene-styrene (ABS); or mixtures thereof. Preferred polyolefins are polyethylene or polypropylene.
Functional additives are materials that contain functional groups such as, but not limited to, hydroxyl, carboxylic acid, anhydride, acyl halide, alkyl halide, aldehyde, alkene, amide, amine, guanidine, malimide, thiol, sulfonate, sulfonic acid, sulfonyl ester, carbodiimide, ester, cyano, epoxide, proline, disulfide, imidazole, imide, imine, isocyanate, isothiocyanate, nitro, or azide. Preferred functional groups are hydroxyl, amine, aldehyde, or carboxylic acid. A particularly preferred functional group is hydroxyl. Examples of functional additives include, but are not limited to, silica powder, silica gel, chopped glass fiber, controlled porous glass (CPG), glass beads, ground glass fiber, glass bubbles, kaolin, alumina oxide, or other inorganic oxides.
Examples of spacers useful in the second embodiment of the invention include, but are not limited to, silanes, functionalized silanes (functional groups such as aldehyde, amino, epoxy, halides, etc.), diamines, alcohols, esters, glycols (such as polyethylene glycol), anhydrides, dialdehydes, terminal difunctionalized polyurethanes, diones, macromer, difunctional and multifunctional polymers with end groups, including, but not limited to, amino, carboxylic acid, ester, aldehyde, or mixtures thereof. In a preferred material, the spacer to which the porous substrate and biological or chemical moiety is attached is of Formula I: 
wherein the bond broken by a wavy line are those between the spacer and the substrate or other moieties; R1 and R2 each independently is hydrogen, substituted or unsubstituted alkyl, aryl, or aralkyl; R3 is a substituted or unsubstituted aliphatic chain or a bond; and n is an integer from about 1 to about 18, preferably, n is an integer from about 1 to about 10, and more preferably from about 2 to about 5.
A variety of chemical and biological moieties can be attached to the porous substrate or spacer of materials of the invention. Examples include, but are not limited to, drugs (e.g., pharmaceuticals), hydrophilic moieties, catalysts, antibiotics, antibodies, antimycotics, carbohydrates, cytokines, enzymes, glycoproteins, lipids, nucleic acids, nucleotides, oligonucleotides, polynucleotides, proteins, peptides, ligand, cells, ribozymes, or combinations thereof.
A specific material of the invention comprises a porous polyethylene substrate having a surface in which a functional additive has been embedded, and a spacer precursor of Formula II covalently attached to at least a portion of said functional additive: 
wherein R1, R2, and R4 each independently is hydrogen, substituted or unsubstituted alkyl, aryl, or aralkyl; R3 is a substituted or unsubstituted aliphatic chain or a bond; X is a group capable of bonding to a biological or chemical moiety, such as OH, NH2, CHO, CO2H, NCO, epoxy, and the like, preferably, X is NH2 or CHO; and n is an integer from about 1 to about 18, preferably, n is an integer from about 1 to about 10, and more preferably from about 2 to about 5.
Still another specific material of the invention comprises a porous polyethylene substrate having a surface in which a functional additive has been embedded, and a spacer of Formula I covalently attached to at least a portion of said functional additive and to a chemical or biological moiety. Preferably, the chemical or biological moiety is a nucleotide, oligonucleotide, polynucleotide, peptide, cell, ligand, or protein.
A third embodiment of the invention encompasses a method of providing a material which comprises: forming a porous substrate comprised of a polymer and a functional additive and having a surface, wherein the surface comprises a region defined by at least some of the functional additive, wherein the region contains at least one functional group; contacting the functional group with a spacer under reaction conditions suitable for the formation of a covalent bond between an atom of the functional group and an atom of the spacer; and contacting the spacer with a chemical or biological moiety under reaction conditions suitable for the formation of a covalent bond or non-covalent bond between an atom of the spacer and an atom of the chemical or biological moiety.
In a preferred method, the functional group is hydroxyl, carboxylic acid, anhydride, acyl halide, alkyl halide, aldehyde, alkene, amide, amine, guanidine, malimide, thiol, sulfonate, sulfonyl halide, sulfonyl ester, carbodiimide, ester, cyano, epoxide, proline, disulfide, imidazole, imide, imine, isocyanate, isothiocyanate, nitro, or azide. Preferred functional groups are hydroxyl, amine, aldehyde, and carboxylic acid.
A fourth embodiment of the invention encompasses a method of providing a material which comprises: forming a porous substrate comprised of a polymer and a functional additive and having a surface, wherein the surface comprises a region defined by at least some of the functional additive, wherein the region contains at least one hydroxyl group; and contacting the hydroxyl group with a compound of Formula II: 
wherein R1, R2, R4, X, and n are as defined above, under conditions suitable for the formation of a material of Formula III: 
wherein R1, R2, X, and n are as defined above for Formula II; and Surface is the surface of the substrate.
The porous substrate may be formed by at least two methods. In one method, beads are sintered together with other polymer beads prior to attaching compounds of Formula II or IV. In another method, compounds of Formula II or IV are attached to the surface of beads prior to sintering the beads to form the porous substrate.
In a specific method of this embodiment, the material of Formula III is contacted with a chemical or biological moiety having an amine group if X is an aldehyde or carboxylic acid, or a chemical or biological moiety having an aldehyde or carboxylic acid group if X is an amine, under reaction conditions suitable for the formation of a material of Formula IV: 
wherein R1, R2, R3, and n are defined as above for Formula II; R is the porous substrate surface and Moiety is a chemical or biological moiety.
In another specific method of this embodiment, the material of Formula IV wherein X is NH2 is contacted with a compound of Formula V:
Z-Spacer-Zxe2x80x83xe2x80x83Formula V
wherein Spacer is a hydrophilic segment and Z is a terminal group capable of covalently or non-covalently bonding to proteins, amino acids, oligonucleotides, and the like, under reaction conditions suitable for the formation of a material of Formula VI: 
wherein R is the surface of the porous substrate; and R1, R2, and n are defined as above for Formula II.
Preferably, the Spacer is a hydrophilic polyurethane, polyethylene glycol, or polyelectrolytes with terminal groups (Z) capable of bonding to proteins, amino acids, oligonucleotides wherein Z includes, but is not limited to, isocyanurate, aldehydes, amines, carboxylic acids, N-hydroxysuccimide, and the like.
A sixth embodiment of the invention encompasses a method of controlling the functionalization of a sintered polyolefin substrate which comprises: forming a mixture of polyolefin particles and particles of a functional additive; and sintering the mixture; wherein the functional additive comprises functional groups and the concentration of functional additive in the mixture is approximately proportional to the density of functional groups on a surface of the sintered polyolefin substrate. In a preferred embodiment, the functional additive is silica powder, silica gel, chopped glass fiber, controlled porous glass (CPG), glass beads, ground glass fiber, glass bubbles, kaolin, alumina oxide, or other inorganic oxides.
As used herein and unless otherwise indicated, the term xe2x80x9calkylxe2x80x9d includes saturated mono- or di-valent hydrocarbon radicals having straight, cyclic or branched moieties, or a combination of the foregoing moieties. An alkyl group can include one or two double or triple bonds. It is understood that cyclic alkyl groups comprise at least three carbon atoms.
As used herein and unless otherwise indicated, the term xe2x80x9caralkylxe2x80x9d includes an aryl substituted with an alkyl group or an alkyl substituted with an aryl group. An example of aralkyl is the moiety xe2x80x94(CH2)pAr, wherein p is an integer of from 1 to about 4, 8, or 10.
As used herein and unless otherwise indicated, the term xe2x80x9carylxe2x80x9d includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
As used herein and unless otherwise indicated, the term xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro, chloro, or bromo.
As used herein and unless otherwise indicated, the term xe2x80x9cnon-covalentxe2x80x9d when used to describe a bond, means a bond formed by ionic interactions, Van der Waals interactions, hydrogen bonding interactions, steric interactions, hydrophilic interactions, or hydrophobic interactions between two atoms or molecules.
As used herein and unless otherwise indicated, the term xe2x80x9csubstituted,xe2x80x9d when used to describe a chemical moiety, means that one or more hydrogen atoms of that moiety are replaced with a substituent. Examples of substituents include, but are not limited to, alkyl and halo.
As used herein and unless otherwise indicated, the term xe2x80x9cheteroarylxe2x80x9d means an aryl group wherein at least one carbon atom has been replaced with an O, S, P, Si, or N atom.
As used herein and unless otherwise indicated, the terms xe2x80x9cheterocyclic groupxe2x80x9d and xe2x80x9cheterocyclexe2x80x9d include aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S, P, Si, or N. Non-aromatic heterocyclic groups must have at least 3 atoms in their ring system, but aromatic heterocyclic groups (i.e., heteroaryl groups) must have at least 5 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties. An example of a 3 membered heterocyclic group is epoxide, and an example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl, and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the compounds listed above, may be C-attached or N-attached where such attachment is possible. For instance, a group derived from pyrrole can be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
As used herein, unless otherwise indicated, the term xe2x80x9cpolyelectrolytexe2x80x9d means a polymer having electronic charges. The polyelectrolyte may exist in a complex form, which is also called symplexes. Polyelectrolytes are divided into polyacids, polybases, and polyampholytes. Depending on the charge density in the chain, polyelectrolytes are divided into weak and strong. The charge of weak polyelectrolytes is determined by dissociation constants of ionic groups and pH of the solution. Strong polyelectrolytes in water solutions are mostly ionized independent of the solution""s pH. Typical weak polyacid polyelectrolytes include, but are not limited to, poly(acrylic acid) and poly(methacrylic acid). Strong polyacid polyelectrolytes include, but are not limited to, poly(ethylenesulfonic acid), poly(styrenesulfoinic acid), and poly(phosphoric acid). Weak polybase polyelectrolytes include, but are not limited to, poly(4-vinylpyridine), polyethyleneimine (PEI), and polyvinylamine. Strong polybase polyelectrolytes can be obtained by alkylation of nitrogen, sulfur, or phosphorus atoms of weak polybase polyelectrolytes. See xe2x80x9cConcise Polymeric Materials Encyclopediaxe2x80x9d (Joseph C. Salamone, 1999 by CRC Press LLC, ISBN 0-84932-226-X, pages 1140-1141).